Takagi Tomohisa, Naito Yuji, Ichikawa Hiroshi, Tomatsuri Naoya, Katada Kazuhiro, Isozaki Yutaka, Kuroda Masaaki, Kokura Satoshi, Yoshida Norimasa, Yoshikawa Toshikazu
Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Redox Rep. 2004;9(6):376-81. doi: 10.1179/135100004225006911.
Recent studies have demonstrated the anti-inflammatory action of 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)), a derivative of the PGD(2) metabolic pathway. Acute inflammation, including neutrophil activation, plays a critical role in the pathogenesis of ischemia-reperfusion (I/R). The aim of the present study was to determine the effect of 15d-PGJ(2) on I/R-induced gastric mucosal injury in rats.
Gastric mucosal damage was induced in male Wistar rats by clamping the celiac artery for 30 min followed by reperfusion. 15d-PGJ(2) (0.01-1.0 mg/kg) was given to the rats intraperitoneally 1 h before the vascular clamping. The area of gastric mucosal erosions (erosion index) was measured. Thiobarbituric acid reactive substances (TBARS) and tissue-associated myeloperoxidase (MPO) activity were measured in the gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The expression of tumor necrosis factor-alpha (TNF-alpha) in gastric mucosa was measured by ELISA. In addition, to elucidate whether the protective effects of 15d-PGJ(2) are related to the activation of the PPAR-gamma receptor, we also investigated the effects of a PPAR-gamma antagonist, GW9662.
After 60 min of reperfusion, the area of gastric erosion index had significantly increased from the mean basal levels. The increase in the erosion index was significantly inhibited by pretreatment with 15d-PGJ(2) in a dose-dependent manner. On the other hand, GW9662 reversed the protective effect of 15d-PGJ(2). The concentration of TBARS and MPO activity in the gastric mucosa were both significantly increased after I/R, and pretreatment with 15d-PGJ(2) significantly reduced these increases. The TNF-alpha content was significantly higher in the I/R group than in the sham-operated group. However, the increase in TNF-alpha was significantly inhibited by pretreatment with 15d-PGJ(2).
15d-PGJ(2) significantly inhibited the severity of acute gastric mucosal injury induced by I/R in rats through PPAR-gamma-dependent mechanisms. This effect may be due, in part, to a reduction in the infiltration of neutrophils into the gastric mucosa, possibly via the inhibition of inflammatory cytokine.
最近的研究表明，15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）具有抗炎作用，它是前列腺素D2代谢途径的一种衍生物。急性炎症，包括中性粒细胞活化，在缺血再灌注（I/R）的发病机制中起关键作用。本研究的目的是确定15d-PGJ2对I/R诱导的大鼠胃黏膜损伤的影响。
通过夹闭雄性Wistar大鼠的腹腔动脉30分钟，然后再灌注，诱导胃黏膜损伤。在血管夹闭前1小时，给大鼠腹腔注射15d-PGJ2（0.01 - 1.0 mg/kg）。测量胃黏膜糜烂面积（糜烂指数）。测定胃黏膜中硫代巴比妥酸反应物质（TBARS）和组织相关髓过氧化物酶（MPO）活性，作为脂质过氧化和中性粒细胞浸润的指标。通过酶联免疫吸附测定法（ELISA）测量胃黏膜中肿瘤坏死因子-α（TNF-α）的表达。此外，为了阐明15d-PGJ2的保护作用是否与过氧化物酶体增殖物激活受体-γ（PPAR-γ）受体的激活有关，我们还研究了PPAR-γ拮抗剂GW9662的作用。
再灌注60分钟后，胃糜烂指数面积较平均基础水平显著增加。15d-PGJ2预处理以剂量依赖方式显著抑制了糜烂指数的增加。另一方面，GW9662逆转了15d-PGJ2的保护作用。I/R后胃黏膜中TBARS浓度和MPO活性均显著增加，15d-PGJ2预处理显著降低了这些增加。I/R组中TNF-α含量显著高于假手术组。然而，15d-PGJ2预处理显著抑制了TNF-α的增加。
15d-PGJ2通过PPAR-γ依赖性机制显著抑制I/R诱导的大鼠急性胃黏膜损伤的严重程度。这种作用可能部分归因于中性粒细胞向胃黏膜浸润的减少，可能是通过抑制炎性细胞因子实现的。
